TIMENTIN

GlaxoSmithKline LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use TIMENTIN safely and effectively. See full prescribing information for TIMENTIN. TIMENTIN (ticarcillin disodium and clavulanate potassium) for InjectionTIMENTIN (ticarcillin disodium and clavulanate potassium) for Injection: Pharmacy Bulk PackageTIMENTIN (ticarcillin disodium and clavulanate potassium) Injection: GALAXY Container Initial U.S. Approval: 1985INDICATIONS AND USAGETo reduce the development of drug-resistant bacteria and maintain the effectiveness of TIMENTIN and other antibacterial drugs, TIMENTIN should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.TIMENTIN is a combination of a β‑lactam antibacterial and a β‑lactamase inhibitor indicated for the treatment of the following infections due to designated susceptible bacteria: •Septicemia (1.1) •Lower respiratory infections (1.2) •Bone and joint infections (1.3) •Skin and skin structure infections (1.4) •Urinary tract infections (1.5) •Gynecologic infections (1.6) •Intra‑abdominal infections (1.7) DOSAGE AND ADMINISTRATIONAdminister TIMENTIN by intravenous infusion (30 minutes). (2)Adults: •Systemic and urinary tract infections: 3.1 g every 4 to 6 hours. (2.1) •Gynecologic infections: 200 to 300 mg/kg/day in divided doses every 4 to 6 hours depending on severity of infection. (2.1) Pediatric Patients: •

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 TIMENTIN INDICATIONS AND USAGE
  • 1.1 Septicemia
  • 1.2 Lower Respiratory Infections
  • 1.3 Bone and Joint Infections
  • 1.4 Skin and Skin Structure Infections
  • 1.5 Urinary Tract Infections
  • 1.6 Gynecologic Infections
  • 1.7 Intra-abdominal Infections
• 2 TIMENTIN DOSAGE AND ADMINISTRATION
  • 2.1 Adults
  • 2.2 Pediatric Patients (≥3 Months of Age)
  • 2.3 Renal Impairment
  • 2.4 Administration and Directions for Use
  • 2.5 Stability
• 3 DOSAGE FORMS AND STRENGTHS
• 4 TIMENTIN CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Anaphylactic Reactions
  • 5.2 Associated Diarrhea
  • 5.3 Convulsions
  • 5.4 Risk of Bleeding
  • 5.5 Potential for Microbial Overgrowth or Bacterial Resistance
  • 5.6 Development of Drug-Resistant Bacteria
  • 5.7 Interference with Laboratory Tests
  • 5.8 Electrolyte Imbalance
• 6 TIMENTIN ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Aminoglycosides
  • 7.2 Probenecid
  • 7.3 Oral Contraceptives
  • 7.4 Effects on Laboratory Tests
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
• 10 OVERDOSAGE
• 11 TIMENTIN DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

TIMENTIN^® is indicated in the treatment of infections caused by susceptible isolates of the designated bacteria in the conditions listed below:

1.1 Septicemia

Septicemia (including bacteremia) caused by β‑lactamase–producing isolates of Klebsiella spp.^*, Escherichia coli ^*, Staphylococcus aureus ^*, or Pseudomonas aeruginosa ^* (or other Pseudomonas species^*)

1.2 Lower Respiratory Infections

Lower respiratory infections caused by β‑lactamase–producing isolates of S. aureus, Haemophilus influenzae ^*, or Klebsiella spp.^*

1.3 Bone and Joint Infections

Bone and joint infections caused by β‑lactamase–producing isolates of S. aureus

1.4 Skin and Skin Structure Infections

Skin and skin structure infections caused by β‑lactamase–producing isolates of S. aureus, Klebsiella spp.^*, or E. coli ^*

1.5 Urinary Tract Infections

Urinary tract infections (complicated and uncomplicated) caused by β‑lactamase–producing isolates of E. coli, Klebsiella spp., P. aeruginosa ^* (or other Pseudomonas spp.^*), Citrobacter spp.^*, Enterobacter cloacae ^*, Serratia marcescens ^*, or S. aureus ^*

1.6 Gynecologic Infections

Endometritis caused by β‑lactamase–producing isolates of Prevotella melaninogenicus ^*, Enterobacter spp. (including E. cloacae ^*), E. coli, Klebsiella pneumoniae ^*, S. aureus, or Staphylococcus epidermidis

1.7 Intra-abdominal Infections

Peritonitis caused by β‑lactamase–producing isolates of E. coli, K. pneumoniae, or Bacteroides fragilis ^* group

* Efficacy for this organism in this organ system was studied in fewer than 10 infections.

1.8 Usage

To reduce the development of drug‑resistant bacteria and maintain the effectiveness of TIMENTIN and other antibacterial drugs, TIMENTIN should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Adults

The usual recommended dosage for systemic and urinary tract infections for adults is 3.1 grams of TIMENTIN (3 grams ticarcillin and 100 mg clavulanic acid) given every 4 to 6 hours.

For gynecologic infections, TIMENTIN should be administered as follows (based on ticarcillin content): Moderate infections, 200 mg/kg/day in divided doses every 6 hours; severe infections, 300 mg/kg/day in divided doses every 4 hours.

For patients weighing less than 60 kg, the recommended dosage is 200 to 300 mg/kg/day given in divided doses every 4 to 6 hours.

The duration of therapy depends upon the severity of infection. The usual duration is 10 to 14 days; however, in difficult and complicated infections, more prolonged therapy may be required.

2.2 Pediatric Patients (≥3 Months of Age)

Patients <60 kg: Mild to moderate infections, 200 mg/kg/day based on ticarcillin content in divided doses every 6 hours; severe infections, 300 mg/kg/day in divided doses every 4 hours.

Patients ≥60 kg: Mild to moderate infections, 3.1 grams every 6 hours; severe infections, 3.1 grams every 4 hours.

2.3 Renal Impairment

For patients with renal insufficiency, an initial loading dose of 3.1 grams should be followed by doses based on creatinine clearance and type of dialysis as indicated in Table 1.

^a To calculate creatinine clearance¹ from a serum creatinine value use the following formula:

C_cr = (140–Age) (weight in kg)/72 x S_cr (mg/100 mL)

This is the calculated creatinine clearance for adult males; for females it is 15% less.

^b Based on ticarcillin content.

2.4 Administration and Directions for Use

TIMENTIN should be administered by intravenous infusion over a 30-minute period.

Directions for Reconstitution and Further Dilution: 3.1‑gram Glass Vials: The 3.1‑gram vial should be reconstituted by adding approximately 13 mL of Sterile Water for Injection, USP, or Sodium Chloride Injection, USP, and shaking well. When dissolved, the concentration of ticarcillin will be approximately 200 mg/mL with a corresponding concentration of 6.7 mg/mL for clavulanic acid. The color of reconstituted solutions of TIMENTIN normally ranges from light to dark yellow, depending on concentration, duration, and temperature of storage.

The dissolved drug should be further diluted to desired volume using the recommended solution listed under Stability [see Dosage and Administration (2.5)] to a concentration between 10 mg/mL to 100 mg/mL.

Pharmacy Bulk Package: The container closure may be penetrated only one time utilizing a suitable sterile transfer device or dispensing set that allows measured distribution of the contents. A sterile substance that must be reconstituted prior to use may require a separate closure entry.

Restrict use of Pharmacy Bulk Packages to an aseptic area such as a laminar flow hood.

Reconstituted contents of the vial should be withdrawn immediately. However, if this is not possible, aliquoting operations must be completed within 4 hours of reconstitution. Discard the reconstituted stock solution 4 hours after initial entry.

Add 76 mL of Sterile Water for Injection, USP, or Sodium Chloride Injection, USP, to the 31‑gram Pharmacy Bulk Package and shake well. For ease of reconstitution, the diluent may be added in 2 portions. Each 1 mL of the resulting concentrated stock solution contains approximately 300 mg of ticarcillin and 10 mg of clavulanic acid.

The desired dosage should be withdrawn from the stock solution and further diluted to desired volume using the recommended solution listed under Stability [see Dosage and Administration (2.5)] to a concentration between 10 mg/mL to 100 mg/mL.

Directions for Intravenous Infusion: After reconstitution and further dilution and prior to administration, TIMENTIN should be inspected visually for particulate matter. If particulate matter is present, the solution should be discarded.

The solution of reconstituted drug may be administered over a 30-minute period by direct infusion or through a Y‑type intravenous infusion set. If this method of administration is used, it is advisable to temporarily discontinue the administration of any other solutions during the infusion of TIMENTIN.

When TIMENTIN is given in combination with another antimicrobial, such as an aminoglycoside, each drug should be given separately in accordance with the recommended dosage and routes of administration for each drug [see Drug Interactions (7.1)].

GALAXY^® Container (PL 2040 Plastic): Prior to administration, TIMENTIN should be inspected visually for particulate matter. If particulate matter is present, the solution should be discarded.

Caution: Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.

Preparation for Administration: See How Supplied/Storage and Handling (16) for thawing and handling instructions:

• •Suspend the container from eyelet support.
• •Remove protector from outlet port at bottom of container.
• •Attach administration set. Refer to complete directions accompanying set.

2.5 Stability

NOTE: TIMENTIN is incompatible with Sodium Bicarbonate.

3.1‑gram Glass Vials: The concentrated stock solution at 200 mg/mL is stable for up to 6 hours at room temperature 21° to 24°C (70° to 75°F) or up to 72 hours under refrigeration 4°C (40°F).

If the concentrated stock solution (200 mg/mL) is held for up to 6 hours at room temperature 21° to 24°C (70° to 75°F) or up to 72 hours under refrigeration 4°C (40°F) and further diluted to a concentration between 10 mg/mL and 100 mg/mL with any of the diluents listed below, then the following stability periods apply.

If the concentrated stock solution (200 mg/mL) is stored for up to 6 hours at room temperature and then further diluted to a concentration between 10 mg/mL and 100 mg/mL, solutions of Sodium Chloride Injection, USP, and Lactated Ringer’s Injection, USP, may be stored frozen –18°C (0°F) for up to 30 days. Solutions prepared with Dextrose Injection 5%, USP, may be stored frozen –18°C (0°F) for up to 7 days. All thawed solutions should be used within 8 hours or discarded. Once thawed, solutions should not be refrozen.

Unused solutions must be discarded after the time periods listed above.

Pharmacy Bulk Package: Aliquots of the reconstituted stock solution at 300 mg/mL are stable for up to 6 hours between 21° and 24°C (70° and 75°F) or up to 72 hours under refrigeration 4°C (40°F). The reconstituted stock solution should be held under refrigeration 4°C (40°F).

If the aliquots of the reconstituted stock solution (300 mg/mL) are held up to 6 hours between 21° and 24°C (70° and 75°F) or up to 72 hours under refrigeration 4°C (40°F) and further diluted to a concentration between 10 mg/mL and 100 mg/mL with any of the diluents listed below, then the following stability periods apply.

If an aliquot of concentrated stock solution (300 mg/mL) is stored for up to 6 hours between 21° and 24°C (70° and 75°F) and then further diluted to a concentration between 10 mg/mL and 100 mg/mL, solutions of Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP, and Sterile Water for Injection, USP, may be stored frozen –18°C (0°F) for up to 30 days. Solutions prepared with Dextrose Injection 5%, USP, may be stored frozen –18°C (0°F) for up to 7 days. All thawed solutions should be used within 8 hours or discarded. Once thawed, solutions should not be refrozen.

Unused solutions must be discarded after the time periods listed above.

GALAXY Container (PL 2040 Plastic): Do not add supplementary medication to the container. The thawed solution is stable for 24 hours at room temperature 22°C (72°F) or for 7 days under refrigeration at 4°C (39°F).

3 DOSAGE FORMS AND STRENGTHS

The 3.1‑gram glass vial of TIMENTIN for Injection is a white to pale yellow sterile powder for reconstitution containing ticarcillin disodium equivalent to 3 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid.

The 31‑gram Pharmacy Bulk Package of TIMENTIN for Injection is a white to pale yellow sterile powder for reconstitution containing ticarcillin disodium equivalent to 30 grams ticarcillin and clavulanate potassium equivalent to 1 gram clavulanic acid.

The 100-mL single-dose GALAXY Container (PL 2040 Plastic) of TIMENTIN is a frozen solution containing ticarcillin disodium equivalent to 3.0 grams ticarcillin and clavulanate potassium equivalent to 0.1 gram clavulanic acid.

4 CONTRAINDICATIONS

TIMENTIN is contraindicated in patients who have a history of hypersensitivity reaction (e.g., anaphylaxis or erythema multiforme) to TIMENTIN or to other β‑lactam antibacterials (e.g., penicillins and cephalosporins).

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylactic Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with TIMENTIN, inquire about previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue TIMENTIN and institute appropriate therapy.

5.2 Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TIMENTIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.3 Convulsions

Patients may experience convulsions when the dose of TIMENTIN exceeds the recommended dose, especially in the presence of impaired renal function [see Adverse Reactions (6.2), Overdosage (10)].

5.4 Risk of Bleeding

Some patients receiving β-lactam antibacterials have experienced bleeding associated with abnormalities in coagulation tests. These adverse reactions are more likely to occur in patients with renal impairment. If bleeding manifestations appear, treatment with TIMENTIN should be discontinued and appropriate therapy instituted.

5.5 Potential for Microbial Overgrowth or Bacterial Resistance

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, appropriate measures should be taken.

5.6 Development of Drug-Resistant Bacteria

Prescribing TIMENTIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug‑resistant bacteria.

5.7 Interference with Laboratory Tests

High urine concentrations of ticarcillin may produce false-positive protein reactions (pseudoproteinuria) [see Drug Interactions (7.4)].

Clavulanic acid may cause a nonspecific binding of IgG and albumin by red cell membranes, leading to a false-positive Coombs test [see Drug Interactions (7.4)].

5.8 Electrolyte Imbalance

Hypokalemia has been reported during treatment with TIMENTIN. Serum potassium should be monitored in patients with fluid and electrolyte imbalance and in patients receiving prolonged therapy. The theoretical sodium content is 4.51 mEq (103.6 mg) per gram of TIMENTIN. This should be considered when treating patients requiring restricted salt intake.

6 ADVERSE REACTIONS

The following are discussed in more detail in other sections of the labeling:

• •Anaphylactic Reactions [see Warnings and Precautions (5.1)]
• • Clostridium difficile Associated Diarrhea [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions occurring in ≥1% of 867 patients receiving TIMENTIN 3.1 grams in clinical studies included rash, nausea, diarrhea, and phlebitis at the injection site. The most common laboratory abnormalities (≥3%) were elevations in eosinophils, serum aspartate aminotransferase (AST), and serum alanine aminotransferase (ALT).

Available safety data for pediatric patients treated with TIMENTIN demonstrate a similar adverse event profile to that observed in adult patients.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use of TIMENTIN. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These adverse reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to TIMENTIN.

Hypersensitivity Reactions: Skin rash, pruritus, urticaria, arthralgia, myalgia, drug fever, chills, chest discomfort, anaphylactic reactions, and bullous reactions (including erythema multiforme, toxic epidermal necrolysis, and Stevens‑Johnson syndrome).

Central Nervous System: Headache, giddiness, neuromuscular hyperirritability, or convulsive seizures.

Gastrointestinal Disturbances: Disturbances of taste and smell, stomatitis, flatulence, nausea, vomiting and diarrhea, epigastric pain, and pseudomembranous colitis have been reported. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment [see Warnings and Precautions (5.2)].

Hemic and Lymphatic Systems: Thrombocytopenia, leukopenia, neutropenia, eosinophilia, reduction of hemoglobin or hematocrit, and prolongation of prothrombin time and bleeding time.

Abnormalities of Hepatic Function Tests: Elevation of AST, ALT, serum alkaline phosphatase, serum LDH, and serum bilirubin. There have been reports of transient hepatitis and cholestatic jaundice, as with some other penicillins and some cephalosporins.

Renal and Urinary Effects: Hemorrhagic cystitis, elevation of serum creatinine and/or BUN, hypernatremia, reduction in serum potassium, and uric acid.

Local Reactions: Pain, burning, swelling, and induration at the injection site and thrombophlebitis with intravenous administration.

7 DRUG INTERACTIONS

7.1 Aminoglycosides

The mixing of TIMENTIN with an aminoglycoside in solutions for parenteral administration can result in substantial inactivation of the aminoglycoside.

7.2 Probenecid

Probenecid interferes with the renal tubular secretion of ticarcillin, thereby increasing serum concentrations and prolonging serum half‑life of ticarcillin. Probenecid does not affect the serum levels of clavulanic acid.

7.3 Oral Contraceptives

Ticarcillin disodium/clavulanate potassium may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

7.4 Effects on Laboratory Tests

High urine concentrations of ticarcillin may produce false‑positive protein reactions (pseudoproteinuria) with certain methods. The bromphenol blue reagent strip test has been reported to be a reliable method for testing protein reactions [see Warnings and Precautions (5.7)].

Clavulanic acid in TIMENTIN may cause a nonspecific binding of IgG and albumin by red cell membranes, leading to a false‑positive Coombs test. A positive Coombs test should be interpreted with caution during treatment with TIMENTIN [see Warnings and Precautions (5.7)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B.

Reproduction studies have been performed in rats given doses up to 1,050 mg/kg/day (approximately half of the recommended human dose based on body surface area) and have revealed no evidence of harm to the fetus due to TIMENTIN. There are, however, no adequate and well‑controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether ticarcillin or clavulanic acid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TIMENTIN is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of TIMENTIN have been established in the age group of 3 months to 16 years. Use of TIMENTIN in these age groups is supported by evidence from adequate and well‑controlled studies of TIMENTIN in adults with additional efficacy, safety, and pharmacokinetic data from both comparative and non‑comparative studies in pediatric patients. There are insufficient data to support the use of TIMENTIN in pediatric patients under 3 months of age.

If meningitis is suspected or documented, an alternative agent with demonstrated clinical efficacy in this setting should be used.

8.5 Geriatric Use

An analysis of clinical studies of TIMENTIN was conducted to determine whether subjects aged 65 and older respond differently from younger subjects. Of the 1,078 subjects treated with at least one dose of TIMENTIN, 67.5% were <65 years old, and 32.5% were ≥65 years old. No overall differences in safety or efficacy were observed between older and younger subjects, and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.3)].

TIMENTIN contains 103.6 mg (4.51 mEq) of sodium per gram of TIMENTIN. At the usual recommended doses, patients would receive between 1,285 and 1,927 mg/day (56 and 84 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.

8.6 Renal Impairment

Ticarcillin is predominantly excreted by the kidney [see Clinical Pharmacology (12.3)]. Dosage adjustments should be made for patients with renal impairment [see Dosage and Administration (2.3)].

10 OVERDOSAGE

In case of overdosage, discontinue TIMENTIN, treat symptomatically, and institute supportive measures as required. Ticarcillin and clavulanic acid may be removed from circulation by hemodialysis.

11 DESCRIPTION

TIMENTIN (ticarcillin disodium and clavulanate potassium) for Injection, 3.1‑gram glass vial, 31‑gram Pharmacy Bulk Package, and TIMENTIN (ticarcillin disodium and clavulanate potassium) Injection in the GALAXY Container (PL 2040 Plastic) are a combination of ticarcillin disodium and the β‑lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid) for intravenous administration. Ticarcillin is derived from the basic penicillin nucleus, 6‑amino‑penicillanic acid.

Chemically, ticarcillin disodium is N-(2-Carboxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-6-yl)-3-thiophenemalonamic acid disodium salt and may be represented as: